Transcript First clinical experience with whole-body PET/MR - Indico

Targeting receptors of
neurotensin and bombesin
Franz Buchegger, David Viertl, Thierry Stora, Léo Bühler, Helmut R. Maecke, Marek
Kosinski, Sébastien Baechler, Raymond Miralbell, John O. Prior and Rosalba Mansi
Departments of Nuclear Medicine, Radio-Oncology, Institute of Radiation Physics and Surgical Research Unit,
Lausanne and Geneva University Hospitals, European Organization for Nuclear Research, CERN Medicis,
Department of Organic Chemistry, Vrije Universiteit Brussels and Department of Nuclear Medicine, University
Hospital of Freiburg
CERN Medicis - Oct 2014
1.
68Ga-DOTA-octreotate
2.
68Ga-NODAGA-RGDyK,
3.
68Ga-NODAGA-MJ9,
(collaboration w. SWAN, Bern), neuroendocrine tumors.
targeting avb3 integrin, (neovascularization, diverse
tumors, atheromatous lesions).
bombesin analog with antagonist activity, selected by Prof
H.R. Maecke, Freiburg, DE, and Dr R. Mansi, Basel. Study in prostate cancer
patients (open) and breast cancer patients (in preparation).
4. Different Neurotensine analogs conjugated to NODAGA/DOTA chelators are
studied in vivo in collaboration with Prof D. Tourwé, Bruxelles.
Neurotensin and bombesin ligand-receptor
systems evolved from a common ancestor
•The neurotensin and GRP ligand /receptor systems are both G-protein
coupled, show similar distributions in the central nervous system and in
gastrointestinal tissues and exhibit similar functionalities.
• Neurotensin (NT) has been shown to induce EGFR-, c-Src- and
Stat5b-dependent proliferation of prostate cancer PC-3, while a
commercial NT antagonist SR-48692 (Sanofi Research) tested on the
breast cancer cell line MDA-MB-231 inhibited its growth.
• SR-48692 is a radiosensitizer (shown on PC-3 tumor grafts).
• Bombesin promotes breast cancer cells MDA-MB-231. Bombesin
antagonist RC-3095 and RC-3940-II (peptides) inhibit growth of
MDA-MB231.
Structural similarities of the G-protein coupled receptors
of neurotensin and gastrin releasing peptide (GRP, bombesin)
T. Nakagawa et al. Biochem Pharmacol 69 (2005) 579–593
« Structure of the agonist-bound neurotensin
receptor ». Jim F. White et al
N AT U R E ; V O L 4 9 0 ; 2 5 O C T O B E R 2 0 1 2
We previously performed a SPECT imaging study with
99mTc-tricarbonyl-NT-XI in patients scheduled for surgery
of ductal pancreatic adenocarcinoma
Buchegger et al, J Nucl Med 2003; 44:1649–1654
Tissue activities expressed in %ID/g x104, corrected for physical
half-life of isotope. Numbers in parentheses represent tumor-tonormal tissue radioactivity ratios.
Different NT-chelate conjugates have been studied compared here
with previously selected 99mTc-labeled peptides of neurotensin
99mTc-NT
-XI
99mTc-NT
-XIX
(NaHis)Ac-Lys-(CH2NH)-Arg-Pro-Tyr-Tle-Leu
(NaHis)Ac-Arg-(NMe)Arg-Pro-Dmt-Tle-Leu
V Maes, E Garcia-Garayoa, P Bläuenstein and D Tourwé: J. Med. Chem. 2006, 49, 1833-1836
DOTA-NT-XIX
NODAGA-NT20.3
DOTA-NT20.3
DOTA-NT20.3- (modified)
DOTA-Arg-(NMe)Arg-Pro-Dmt-Tle-Leu √
Ac-Lys(NODAGA)-Pro-(NMe)Arg-Arg-Pro-Tyr-Tle-Leu √
Ac-Lys(DOTA)-Pro-(NMe)Arg-Arg-Pro-Tyr-Tle-Leu √
Ac-Lys(DOTA)-Pro-(NMe)Arg-Arg-Pro-Tyr-Ile-Leu √
NODAGA-PEG-NT-X
NODAGA-PEG-Arg-Arg-Pro-Tyr-Tle-Leu √
NODAGA-PEG-NT-X’
NODAGA-PEG-Arg-Arg-Pro-Dmt-Tle-Leu √
NODAGA-PEG-NT-XII
(NODAGA-PEG-NT-X’’ )
Sequence of natural
NT and NT(8-13)
NODAGA-PEG-Arg-(NMe)Arg-Pro-Tyr-Tle-Leu √
(NODAGA-PEG-Arg-(CH2NH)-Arg-Pro-Tyr-Tle-Leu )
Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu
68Ga-NODAGA-NT20.3
Analog to the INSERM :
DOTA-NT20.3 (patent)
Interesting uptake was observed
in reference tumor HT-29
and in co-transplanted
prostate cancer PC-3 as well as
in normal intestines compared with
the 99mTc-NT-XIX or the
111In-DOTA-NT20.3 (published by INSERM)
and 68Ga-DOTA-NT20.3 (our results)
68Ga-NODAGA-PEG-NT-X
Looked good, has been prepared in
GMP quality !
PA= Phosphoramidon
(enzyme inhibitor;
B.A. Nock et al
JNM 2014;55:121-7)
Summary on NT analogs
- NODAGA-NT20.3, analog to the French INSERM DOTA-NT20.3 (patented by
INSERM) showed good tumor uptake.
- NODAGA-PEG-NT-X and derivatives with single further modifications (NT-X’, NTXII) gave high tumor-to-normal tissue ratios. With 68Ga-NODAGA-PEG-NT-X we
have made a preclinical dosimetry and a tolerance study in mice and produced it in
GMP quality (ready for a clinical study).
- Prostate cancer PC-3 expresses both bombesin and neurotensin receptors in high
amount.
- Pancreas tumors Capan-2 and Mia-PaCa-2 will be tested as new targets expressing
NT receptors (transferred from Douglas Hanahan’s lab).
- Glioblastoma lines LN229, U-87, U-251 are other potential targets of neurotensin
•
Ligands of gastrin releasing peptide (GRP) have been developed as analogs of
bombesin. Bombesin was first isolated from skin of the frog “bombina”.
Bombesin is very similar to the human GRP. In human, a strong expression of
GRP receptors was found in the central nervous system and neuroendocrin
gastrointestinal tissues and cancer, particularly in prostate and breast cancer
(studies by Prof. J.C. Reubi, US and Bern).
•
A comparative PET/CT study on 18F-choline and 11C-acetate has been performed
at HUG on 35 patients. A first analysis in 23 patients has been published. It
showed a similar behavior of both tracers.
•
A PET/CT study on evolution of tumor hypoxia under radiation therapy of
prostate cancer shown by F-MISO is open at HUG. (comparison with F-Choline
or 11C-acétate).
GRP and GRP receptors and bombesin analogs with agonist and antagonist
activity - the similarity with neurotensin
•
•
•
•
•
Bombesin is a peptide of 14 amino acids while GRP is composed of 27 amino
acids.
GRP receptors (GRPr) and its ligand GRP, are frequently co-expressed by the
same cells (autocrine loop), notably in prostate, breast and digestif cancers.
GRPr belongs together with NMBr (neuromedin receptor), BRS-3, NTr1 and
NTR2 to the family of G-protein coupled receptors.
The fragment NTS8-13 of neurotensin bound to the receptor NTr1 has been
resolved by crystallography.
Similar to NTr1, GRPr has 7 transmembrane domains. The 3 extracellular loops
of GRPr form the ligand binding site.
GRP and analogs of bombesin exhibiting agonist and antagonist activity:
GRP :
Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu-Thr-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met
Bombésine :
Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met
GRP antagonist :
D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu
DOTA-RM6 :
DOTA-PEG4-(4-amino-1-carboxymethyl-piperidine)-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu
NODAGA-MJ9
NODAGA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu
Pyr= pyroglutamyl; Sta=statine
Two small PC-3 tumors/mouse (grown over 3 weeks), male SCID mice, DOTA-RM6 as used for Tb-152, 3 mice per group
Carcass
TB
Blood
Large bowel
Small bowel
Stomach
Skin
Bone
Muscle
Heart
Spleen
Lung
Kidneys
Liver
Pancreas
% ID/g
50
10 minutes
30 minutes
60 minutes
90 minutes
40
30
20
10
0
Relative organ contributions to the human effective dose (ED) according to Olinda; The ED
predicted from mice was confirmed in 5 male patients with less than 10 % difference.
38.2 mSv/MBq
28.3 mSv/MBq
Interval of bladder void : 1 h
0.5 h
Biodistribution after injection
of 8.25 MBq 177Lu-DOTA-RM6
SPECT/CT (clinical imaging device)
%ID/g
PC-3 tumor
Adrenals
Pancreas
Liver
Kidneys
Lung
Spleen (93 mg)
Heart
Muscle
Bone
Skin
Stomach
Small Intest
Large Intest
Blood
Bladder
10.52
0.57
0.60
0.72
1.29
0.13
5.61
0.02
0.01
0.04
0.08
0.08
0.10
1.49
0.11
0.15
Controls without treatment
1
RT 8 Gy (3 fract)
PRRT 50 MBq (5 inj)
RT 8Gy + PRRT 50 MBq
RT 16 Gy (5 fractions)
0.6
PRRT 100 MBq (10 inj)
0.4
0.2
0
0
20
40
60
80
days after treatment initiation
1
Controls without treatment
RT 12 Gy (8 fract)
0.8
survival (Tu < 1 cm3)
survival (Tu < 1 cm3)
0.8
PRRT 80 MBq (8 inj)
RT 12 Gy + PRRT 80 MBq synchrone
0.6
RT 24 Gy (8 fractions)
PRRT 160 MBq (8 inj)
0.4
RT 12 Gy + PRRT 80MBq sequential
0.2
0
0
20
40
60
80
days after treatment initiation
100
120
The CHUV Nuclear Medicine Albira PET/SPECT/CT jointly funded by
FNS and UNIL should be operational in 2 to 3 months.
•
The clinical study of dual PET/CT foreseen for 60 prostate cancer patients at either initial
presentation or recurrence comparing 68Ga-NODAGA-MJ9 with 18F-flurocholine, has confirmed
the dosimetry projection extrapolated from mice and is currently generally open for inclusion.
•
MJ9 exhibiting antagonist activity was predicted not to provoke side effects such as gastrin
release or cellular growth. No side effects were observed in our first 8 patients.
•
DOTA-RM6 can be radiolabeled with positron emitters for PET such as 152Tb or 68Ga, electron
emitters for therapy such as 161Tb or 177Lu, or the a-particle emitter 149Tb (the latter co-emitting
positrons for PET). DOTA-RM6 radiolabeled with these different radioisotopes should allow
approaching therapy studies under well controlled conditions searching for curative approaches.
•
Our first experiments showed that external beam radiation therapy (RT) combines favorably with
systemic radiation therapy with DOTA-bombesin labeled with an electron emitter (PRRT).
•
Bombesin in conjunction with neurotensin and neurotensin receptor expression of PC-3 cells can
allow double receptor targeting with both peptide analogs for a co-operative therapy study (the
neurotensin antagonist SR48692 has been shown to be a radiosensitizer on PC-3 tumors (Cancer
Research) or could be used as unlabeled growth inhibitor) or to use neurotensin analogs for imaging
independent of the therapy with high amounts of bombesin conjugates. Repeat imaging under
therapy requires an on-site micro-PET/SPECT/CT. It will be installed at CHUV this month.
Thanks for support to :
Fondation pour les recherches médicales et
biologiques sur le cancer, Genève.
Cellex Foundation, Barcelona (Clinical study support).
Dr Catherine Servis, Protein and Peptide Chemistry
Facility, Department of Biochemistry, UNIL, for the
collaboration in peptide design and production.
and a great thanks you for your attention !